Biology subjects

Mortimer, T.

Publications and source records attributed to Mortimer, T..

3 recordsLinked to original sources

bioRxiv2022

Interrogating Metabolic Interactions Between Skeletal Muscle and Liver Circadian Clocks In Vivo

Expressed throughout the body, the circadian clock system achieves daily metabolic homeostasis at every level of physiology, with clock disruption associated with metabolic disease (1, 2). Molecular clocks present in the brain, liver, adipose, pancreas and skeletal muscle each contribute to glucose homeostasis (3). However, it is unclear; 1) which organ clocks provide the most essential contributions, and 2) if these contributions depend on inter-organ communication. We recently showed that the liver clock alone is insufficient for most aspects of daily liver glucose handling and requires connections with other clocks (4). Considering the pathways that link glucose metabolism between liver and skeletal muscle, we sought to test whether a clock connection along this axis is important. Using our previous published methodology for tissue-specific rescue of Bmal1 in vivo (4, 5), we now show that in the absence of feeding-fasting cycles, liver and muscle clocks are not sufficient for systemic glucose metabolism, nor do they form a functional connection influencing local glucose handling or daily transcriptional rhythms in each tissue. However, the introduction of a daily feeding-fasting rhythm enables a synergistic state between liver and muscle clocks that leads to restoration of systemic glucose tolerance. These findings reveal limited autonomous capabilities of liver and muscle clocks and highlight the need for inter-organ clock communication for glucose homeostasis which involves at least two peripheral metabolic organs.

cell biology↗

bioRxiv2022

Brain-keratinocyte communication suffices for epidermal daily homeostasis

In mammals, an integrated network of molecular oscillators drives daily rhythms of tissue-specific homeostatic processes. This circadian clock network is required for maintaining health and is compromised by disease and lifestyle choices, such as diet and exercise. However, critical properties of this systemic network, such as which tissues communicate to coordinate their respective programs of daily physiology, and the exact homeostatic processes requiring each communication pathway, remain undefined. To dissect daily inter-tissue communication, we have constructed in mice a minimal clock network comprising only two nodes: the peripheral epidermal clock and the central brain clock. By circadian transcriptomic and functional characterization of this isolated connection, we have identified a previously unknown gatekeeping function of the peripheral tissue clock with respect to systemic inputs. That is, the epidermal clock concurrently integrates and corrects brain signals to ensure timely execution of epidermal daily physiology. Specifying the integrative arm of the clock, we identify that timely cell cycle termination in the epidermal stem cell compartment is dependent upon incorporation of clock-driven signals originating from the brain. Unexpectedly, and in contrast, the epidermal clock corrects potentially disruptive feeding-related signals to ensure that DNA replication occurs at the optimum time of day. Together, we present a novel approach for cataloguing the systemic dependencies of a given tissue, and in turn identify an essential gate-keeping function of peripheral circadian clocks that guarantees tissue homeostasis.

cell biology↗

bioRxiv2022

The central clock suffices to drive the majority of circulatory metabolic rhythms

Life on Earth anticipates recurring 24-h environmental cycles via genetically-encoded molecular clocks active in all mammalian organs. Communication between these clocks is believed to control circadian homeostasis. Metabolism can be considered a form of inter- tissue communication language that results in temporal coordination of systemic metabolism between tissues. Here we characterize the extent to which clocks in different organs employ this means of communication, an area which remains largely unexplored. For this, we analysed the metabolome of serum from mice with tissue-specific expression of the clock gene Bmal1. Notably, having functional hepatic and muscle clocks can only drive a minority (13%) of the oscillating metabolites in circulation. Conversely, limiting Bmal1 expression to Syt10- expressing neurons (which are enriched in the suprachiasmatic nucleus [SCN], the master pacemaker that regulates circadian rhythms) restores rhythms to 57% of circulatory metabolites and 28% of liver transcripts, and rescues glucose intolerance. Importantly, these parameters were also restored in clock-less mice upon rhythmic feeding, indicating that the central clock mainly regulates metabolic rhythms via behavior. These findings explicate the circadian communication between tissues and highlight the importance of the central clock in governing those signals.

physiology↗